L-type Ca2+ channels (LTCCs) play a central role in triggering diverse forms of excitation-response coupling in cells of the heart, skeletal muscle, glands, and brain. Yet, while both excitation-contraction (in cardiac and skeletal muscle tissue) and excitation-secretion coupling (in glands) have been intensively studied, much less is known about excitation-transcription coupling in neurons. This proposal is aimed at elucidating the mechanisms by which different classes of Ca2+ channels link membrane depolarization to nuclear events, focusing largely on LTCCs. Three specific aims are proposed. (1) Characterize alternative pathways for linking cellular activity to CREB phosphorylation, one requiring local submembranous signaling from LTCCs, the other involving global Ca2+ signals generated by non-LTCCs. Understanding how these parallel pathways signal to CREB will help settle a long-standing controversy in the field. Experiments will clarify the cell biological mechanisms that give LTCCs an advantage and others that put non-LTCCs at a disadvantage. (2) Define the voltage and Ca2+ dependence of L-type Ca2+ channel signaling. We have found compelling evidence that signaling to CREB via the local pathway invokes a cooperative mechanism, similar to other forms of excitation-response coupling. Moreover, this mechanism seems to be steeply voltage-dependent but only mildly dependent on blockade of the permeation pathway. Here we will explore the underlying basis of these findings. (3) Clarify how diverse Ca2+ channels, calmodulin and nuclear CREB signaling pathways link physiological stimuli to gene expression. The reductionist experiments in the first two aims lead logically to studying how natural stimuli, such as synaptic depolarizations or action potentials, can activate the local and/or global signaling pathways, and how synaptic signals are conveyed to the nucleus. Thus, in this aim we will explore how physiologically relevant stimuli differentially utilize local and global Ca2+ signaling pathways to activate CREB and CRE-dependent gene expression. Further, we will explore whether local and global Ca2+ signaling pathways regulate distinct or overlapping expression of genes. Gaining a clearer picture of the linkage between Ca2+ channels and CREB signaling will have a favorable impact on understanding how changes in gene expression alter the function of neurons in neural networks. Thus, the research is relevant both to basic excitable cell biology and to disease states such as addiction.